Agrochemical lead optimization by scaffold hopping

Lamberth, Clemens

doi:10.1002/ps.4755

Cited by 89 publications

(97 citation statements)

References 65 publications

(71 reference statements)

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“…In a d d ition , w e n ote th a t m olecu les w ith d iffer en t sca ffold s m a y b e q u ite sim ila r ; in th e ch em in for m a tics liter a tu r e th is is kn ow n a s 'sca ffold h op p in g' (e.g. [65][66][67][68][69][70]).…”

Section: Resultsmentioning

confidence: 99%

Structural similarities between some common fluorophores used in biology and marketed drugs, endogenous metabolites, and natural products

O’Hagan

Kell

2019

Preprint

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St r uct ur al si m i l ar i t i es bet w een som e com m on f l uor oph or es used i n bi ol ogy an d m ar k et ed dr u gs, en dogen ou s m et abol i t es, an d n at u r al pr odu ct s St ev e O'Hagan 1,2 , Dou gl as B. Kel l 1,2,3,4 * 1 School of Chem istr y, 2 M anchester Insti tute of Bi otechnology, The Uni ver si ty of M anchester , 131 Pr incess St, M anchester M1 7DN, UK 3 (and pr esent addr ess): Depar tm ent of Biochem istr y, Institute of Integr ative Biology, Biosciences Building, Univer sity of Liver pool, Cr ow n Str eet, Liver pool L69 7ZB, UK. 4 Novo Nor di sk Foundation Centr e for Biosustainability, Technical Univer sity of Denm ar k, Building 220, Kem itor vet, 2800 Kgs. Lyngby, Denm ar k * Cor r espondence: Douglas Kell, Em ai l: dbk@liv.ac.uk; ABSTRACTBackgr ound: It is kn ow n th a t a t lea st som e flu or op h or es ca n a ct a s 'su r r oga te' su b str a tes for solu te ca r r ier s (SLCs) in volved in p h a r m a ceu tica l d r u g u p ta ke, a n d th is p r om iscu ity is ta ken to r eflect a t lea st a cer ta in str u ctu r a l sim ila r ity. As p a r t of a com p r eh en sive stu d y seekin g th e 'n a tu r a l' su b str a tes of 'or p h a n ' tr a n sp or ter s th a t a lso ser ve to ta ke u p p h a r m a ceu tica l d r u gs in to cells, w e h a ve n oted th a t m a n y d r u gs b ea r str u ctu r a l sim ilar ities to n a tu r al pr od u cts. A cu r sor y in sp ection of com m on flu or op h or es in d ica tes th a t th ey too a r e su r p r isin gly 'd r u g-like', a n d th ey a lso en ter a t lea st som e cells. Som e a r e a lso kn ow n to b e su b str a tes of efflu x tr a n sp or ter s. Con seq u en tly, w e sou gh t to a ssess th e str u ctu r a l sim ila r ity of com m on flu or op h or es to m a r keted d r u gs, en d ogen ou s m a m m a lia n m eta b olites, a n d n a tu r a l p r od u cts. We u sed a set of som e 150 flu or op h or es. Results: Th e gr ea t m a jor ity of flu or op h or es tested exh ib ited sign ifica n t sim ila r ity (Ta n im oto sim ila r ity > 0.75) to a t lea st on e d r u g a s ju d ged via descr ip tor p r op er ties (esp ecia lly th eir a r om a ticity, for id en tifia b le r ea son s th a t w e exp la in ), b y m olecu la r fin ger p r in ts, b y visu a l in sp ection , a n d via th e "q u a n tita tive estim a te of d r u g liken ess" tech n iq u e. It is con clu d ed th a t th is set of flu or op h or es d oes over la p a sign ifica n t p a r t of b oth d r u g sp a ce a n d n a tu r a l p r od u cts sp a ce. Con seq u en tly, flu or op h or es d o in d eed offer a m u ch w id er op p or tu n ity th a n h a d p ossib ly b een r ea lised to b e u sed a s su r r oga te u p ta ke m olecu les in th e com p etitive or tr a n s-stim u la tion a ssa y of m em br a n e tr a n sp or ter a ctivities.KEYW ORDS: d r u gs -n atu r a l p r od u cts -flu or op h or es -sim ila r ity -ch em in for m a tics -Ta n im oto d ista n ce ABBREVI ATI ONS PCA, Pr in cip a l Com p on en ts An a lysis; QED, Qu a n tita tive Estim a te of Dr u g-liken ess; QSAR, Qu a n ...

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Section: Resultsmentioning

confidence: 99%

Structural similarities between some common fluorophores used in biology and marketed drugs, endogenous metabolites, and natural products

O’Hagan

Kell

2019

Preprint

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“…Scaffold hopping was proposed as a promising strategy to look for novel molecular entities with similar three dimensional conformations and properties (Schneider et al, 1999 ). As a shape-based three dimensional structure superposition method, it has been extensively used to generate potential alternatives of known compounds based on the bioisosteric replacement of core motif within molecules (Sun et al, 2012 ; Lamberth, 2017 ). In 2016, Yue et al applied a shape-based scaffold hopping approach to reposition approved drugs targeting the Menin-MLL1 interaction (Yue et al, 2016 ).…”

Section: Wdr5-mll1mentioning

confidence: 99%

Computer-Aided Drug Design in Epigenetics

Zhang

Jiang

et al. 2018

Front. Chem.

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Epigenetic dysfunction has been widely implicated in several diseases especially cancers thus highlights the therapeutic potential for chemical interventions in this field. With rapid development of computational methodologies and high-performance computational resources, computer-aided drug design has emerged as a promising strategy to speed up epigenetic drug discovery. Herein, we make a brief overview of major computational methods reported in the literature including druggability prediction, virtual screening, homology modeling, scaffold hopping, pharmacophore modeling, molecular dynamics simulations, quantum chemistry calculation, and 3D quantitative structure activity relationship that have been successfully applied in the design and discovery of epi-drugs and epi-probes. Finally, we discuss about major limitations of current virtual drug design strategies in epigenetics drug discovery and future directions in this field.

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“…Strategies in scaffold hopping 5 and bioisosteric replacement of functional groups 6 offer great opportunities to explore and optimize many cross-functional parameters in drug design. We aim herein to describe how the chemistry around an underexplored building block from the 1960s was developed towards a novel non-neuronal acting active ingredient against key economic pests, especially those sucking from the phloem of plant vascular bundles in growing shoots.…”

Section: Introductionmentioning

confidence: 99%

Spiro N‐methoxy piperidine ring containing aryldiones for the control of sucking insects and mites: discovery of spiropidion

Muehlebach

Buchholz

Zambach

et al. 2020

Pest Management Science

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BACKGROUND Crop protection solutions for the control of key economic sucking pests derive essentially from neuronal and muscular acting chemistries, wherein neonicotinoid uses largely dominated for the last two decades. Anticipating likely resistance development of some of those arthropod species to this particular class, we intensified research activities on a non‐neuronal site of action targeting insect growth and development some 10 years ago. RESULTS Our innovation path featured reactivation of a scarcely used and simple building block from the 1960s, namely N‐methoxy‐4‐piperidone 3. Its judicious incorporation into the 2‐aryl‐1,3‐dione scaffold of IRAC group 23 inhibitors of fatty acid biosynthesis resulted in novel tetramic acid derivatives acting on acetyl‐coenzyme A carboxylase (ACCase). The optimization campaign focused on modulation of the aryl substitution pattern and understanding substituent options at the lactam nitrogen position of those spiroheterocyclic pyrrolidine‐dione derivatives towards an effective control of sucking insects and mites. This work gratifyingly culminated in the discovery of spiro N‐methoxy piperidine containing proinsecticide spiropidion 1. Following in planta release, its insecticidally active dione metabolite 2 is translaminar and two‐way systemic (both xylem and phloem mobile) for a full plant protection against arthropod pests. CONCLUSION Owing to such unique plant systemic properties, growing shoots and roots actually not directly exposed to spiropidion‐based chemistry after foliar application nevertheless benefit from its long‐lasting efficacy. Spiropidion is for use in field crops, speciality crops and vegetables controlling a broad range of sucking pests. In light of other performance and safety profiles of spiropidion, an IPM fit may be expected. © 2020 Society of Chemical Industry

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Agrochemical lead optimization by scaffold hopping

Cited by 89 publications

References 65 publications

Structural similarities between some common fluorophores used in biology and marketed drugs, endogenous metabolites, and natural products

Structural similarities between some common fluorophores used in biology and marketed drugs, endogenous metabolites, and natural products

Computer-Aided Drug Design in Epigenetics

Spiro N‐methoxy piperidine ring containing aryldiones for the control of sucking insects and mites: discovery of spiropidion

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